The regulation of adenylate cyclase and phosphodiesterase activity by neuro-transmitters, prostaglandins, adenosine, calmodulin, guanyl nucleotides, receptors, P-sites, and other factors has been investigated. Such data are fundamental to an understanding of the role of cyclic nucleotides in the central nervous system. Selective ligands have been employed for the characterization of beta1- and beta2-adrenergic, alpha1-adrenergic, A1 and A2-adenosine receptors regulating adenylate cyclase in brain tissue, and for the characterization of the inhibitory adenosine P-site associated with adenylate cyclase. Activation of cyclic AMP-systems in brain slices by x-adrenergic, H1-histamine and serotonin receptors is dependent on calcium ions and probably involves an indirect facilitory effect on the coupling of A2-adenosine, beta-adrenergic and H2-histamine receptors with adenylate cyclase. Prostaglandins appear to enhance availability of calcium to such systems.